Inflammation is a process resulting from the dilation and increased permeability of blood vessels at site of injury or infection. Chemokines and cytokines released at the site increase the expression of cell surface proteins on endothelial cells, allowing circulating leukocytes to stick to the vessel wall and migrate to the site of injury/infection within the tissue. These cell surface proteins, termed “cell adhesion molecules” allow the interaction between the leukocytes and the endothelial cells, and mediate the migration of leukocytes into the tissue. Additionally, cell adhesion molecules are required for many of the cell-to-cell interactions in the inflammatory and immune responses. There are three classes of adhesion molecules: selectins, integrins and immunmoglobulin-related proteins which can be expressed on leukocytes and endothelial cells. Several of the adhesion molecules, including E-selectin and ICAM, are induced by cytokines such as IL-1 and TNF, and their expression is mediated by the transcriptional factor, NF-κB.
Sustained or inappropriate expression of adhesion molecules can lead to inflammatory or autoimmune disorders. Exaggerated expression of E-selectin and/or ICAM can result in chronic inflammation and has been associated with several inflammatory or autoimmune disorders. Therefore, inhibitors of cell adhesion molecules may be useful for the treatment of these diseases.
Inflammatory and autoimmune diseases are not well managed by current therapy and developments of better drugs are widely pursued. For example, rheumatoid arthritis is a state of chronic inflammation within the joint characterized by cartilage and bone destruction. Traditional therapies for inflammatory or autoimmune disease, such as rheumatoid arthritis, include nonsteroidal anti-inflammatory drugs and salicylates, gold compounds, hydroxychloroquine, sulfasalazine, corticosteroids, oral penicillamines, and cytotoxic or immunosuppressive drugs. However, many of these therapies are not always sufficiently effective and have resulted in serious side effects. More recently, injectable forms of TNFα neutralizing proteins have been successfully marketed for the treatment of rheumatoid arthritis and Crohn's Disease, however, an orally available inhibitor has not been developed for these inflammatory or autoimmune diseases.
Able to inhibit NF-κB activation through inhibition of the IKKβ protein kinase, 1H-Imidazo[4,5-b]pyridin-5-amine, 7-[5-[(cyclohexylmethylamino)-methyl]-1H-indol-2-yl]-2-methyl (ER-807447) is a potent anti-cytokine/anti-inflammatory agent. Published PCT application WO 2004/06336 A2 and published U.S. application 2004/0186127 A1 disclose ER-807447 as a member of a novel class of deazapurine therapeutic agents having antiflammatory/autoimmune and anti-proliferative effects (both of these published applications are incorporated here by reference). These deazapurine therapeutic agents are orally available and are free of serious side effects.
Although therapeutic efficacy is the primary concern for a therapeutic agent, the salt and crystal form of a drug candidate can be critical to its development. Each salt or each crystalline form (polymorph) of a drug candidate can have different physical and chemical properties, for example, solubility, stability, or the ability to be reproduced. These properties can impact the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate form for further drug development, can reduce the term and the cost of that development.
Obtaining pure crystalline forms is extremely useful in drug development. It permits better characterization of the drug candidate's chemical and physical properties. The crystalline form may possess more favorable pharmacology than the amorphous form or be easier to process. It may also possess more storage stability.
The solid state physical properties of a drug candidate influence its selection as a pharmaceutical active ingredient and the choice of form for its pharmaceutical composition. One such physical property, for example, is the flowability of the solid, before and after milling. Flowability affects the ease with which the material is handled during processing into a pharmaceutical composition. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate. Another important solid state property of a pharmaceutical compound is its dissolution rate in aqueous fluid. The rate of dissolution of an active ingredient in a patient's gastrointestinal fluid may have therapeutic consequences since it impacts the rate at which an orally-administered active ingredient may reach the patient's bloodstream.
These practical physical properties are influenced by the conformation and orientation of molecules in the unit cell of the crystalline compound. The crystalline (or polymorphic) form often has different thermal behavior different from the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some polymorphic forms from others. A crystalline form or a particular polymorphic form generally possesses distinct crystallographic and spectroscopic properties detectable by powder X-ray diffraction (XRD), single crystal X-ray crystallography, and infrared spectrometry among other techniques.